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Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics are “live microorganisms that are beneficial to the health of the host when administered in sufficient quantities”. It has been demonstrated that probiotics can prevent or treat a variety of human diseases; however, their ability to mitigate MC-LR-induced intestinal harm has not yet been investigated. The objective of this study was to determine whether probiotics can mitigate MC-LR-induced intestinal toxicity and its underlying mechanisms. We first evaluated the pathological changes in colorectal tissues using an animal model with sub-chronic exposure to low-dose MC-LR, HE staining to assess colorectal histopathologic changes, qPCR to detect the expression levels of inflammatory factors in colorectal tissues, and WB to detect the alterations on CSF1R signaling pathway proteins in colorectal tissues. Microbial sequencing analysis and screening of fecal microorganisms differential to MC-LR treatment in mice. To investigate the role of microorganisms in MC-LR-induced colorectal injury, an in vitro model of MC-LR co-treatment with microorganisms was developed. Our findings demonstrated that MC-LR treatment induced an inflammatory response in mouse colorectal tissues, promoted the expression of inflammatory factors, activated the CSF1R signaling pathway, and significantly decreased the abundance of Lactobacillus. In a model of co-treatment with MC-LR and Lactobacillus fermentum (L. fermentum), it was discovered that L. fermentum substantially reduced the incidence of the colorectal inflammatory response induced by MC-LR and inhibited the protein expression of the CSF1R signaling pathway. This is the first study to suggest that L. fermentum inhibits the CSF1R signaling pathway to reduce the incidence of MC-LR-induced colorectal inflammation. This research may provide an excellent experimental foundation for the development of strategies for the prevention and treatment of intestinal diseases in MC-LR.

Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid β-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/β-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice’s serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid β-oxidation.

Microcystin-LR (MC-LR), a cyanotoxin produced by cyanobacteria, induces oxidative stress in various types of cells. Prodigiosin, a red linear tripyrrole pigment, has been recently reported to have antimicrobial, antioxidative, and anticancer properties. How prodigiosin reacts to reactive oxygen species (ROS) induced by MC-LR is still undetermined. This study aimed to examine the effect of prodigiosin against oxidative stress induced by MC-LR in HepG2 cells. Ros was generated after cells were treated with MC-LR and was significantly inhibited with treatment of prodigiosin. In prodigiosin-treated cells, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-related phase II enzyme heme oxygenase-1 (HO-1) were increased. Besides, prodigiosin contributed to enhance nuclear Nrf2 level and repressed ubiquitination. Furthermore, prodigiosin promoted Nrf2 protein level and inhibited ROS in Nrf2 knocked down HepG2 cells. Results indicated that prodigiosin reduced ROS induced by MC-LR by enhancing Nrf2 translocation into the nucleus in HepG2 cells. The finding presents new clues for the potential clinical applications of prodigiosin for inhibiting MC-LR-induced oxidative injury in the future.

Microcystin-LR is a cyclic heptapeptide hepatotoxin produced by harmful cyanobacteria. A panel of microRNAs containing miR-451a were found to be significantly changed in normal human liver cells HL7702 after exposure to microcystin-LR (MC-LR) in our previous study. However, the functions of miR-451a in hepatotoxicity induced by MC-LR remained unclear. The study aimed to investigate the impacts of miR-451a in HL7702 cells following treatment with 5 or 10 μM MC-LR. The comet assay indicated that MC-LR can influence Olive tail moment (OTM) in HL7702 cells. Furthermore, increase of miR-451a significantly repressed DNA damage and the protein expression level of γ-H2AX induced by MC-LR. Moreover, over-expression of miR-451a inhibited the expression level of p-AKT1 protein in cells following treatment by MC-LR. These results showed that miR-451a may protect from MC-LR-induced DNA damage by down-regulating the expression of p-AKT1, which provides new clues for the diagnosis and therapy policies for liver damage induced by MC-LR.